Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Minnesota Supercomputing Institute, 599 Walter Library, 117 Pleasant Street, Minneapolis, MN 55455, USA.
Cereb Cortex. 2024 May 2;34(13):161-171. doi: 10.1093/cercor/bhae044.
Autism spectrum disorder (ASD) is a developmental disorder with a rising prevalence and unknown etiology presenting with deficits in cognition and abnormal behavior. We hypothesized that the investigation of the synaptic component of prefrontal cortex may provide proteomic signatures that may identify the biological underpinnings of cognitive deficits in childhood ASD. Subcellular fractions of synaptosomes from prefrontal cortices of age-, brain area-, and postmortem-interval-matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of data revealed the enrichment of ASD risk genes that participate in slow maturation of the postsynaptic density (PSD) structure and function during early brain development. Proteomic analysis revealed down regulation of PSD-related proteins including AMPA and NMDA receptors, GRM3, DLG4, olfactomedins, Shank1-3, Homer1, CaMK2α, NRXN1, NLGN2, Drebrin1, ARHGAP32, and Dock9 in children with autism (FDR-adjusted P < 0.05). In contrast, PSD-related alterations were less severe or unchanged in adult individuals with ASD. Network analyses revealed glutamate receptor abnormalities. Overall, the proteomic data support the concept that idiopathic autism is a synaptopathy involving PSD-related ASD risk genes. Interruption in evolutionarily conserved slow maturation of the PSD complex in prefrontal cortex may lead to the development of ASD in a susceptible individual.
自闭症谱系障碍（ASD）是一种发育障碍，其发病率不断上升，病因不明，表现为认知缺陷和异常行为。我们假设，对前额叶皮层突触成分的研究可能会提供蛋白质组学特征，从而确定儿童 ASD 认知缺陷的生物学基础。来自患有特发性 ASD 儿童和成人与对照者的年龄、脑区和死后间隔匹配样本的前额叶皮质突触体的亚细胞级分，接受了 HPLC-串联质谱分析。数据分析显示，ASD 风险基因参与突触后密度（PSD）结构和功能的缓慢成熟，这些基因在大脑早期发育过程中得到了富集。蛋白质组学分析显示，包括 AMPA 和 NMDA 受体、GRM3、DLG4、olfactomedins、Shank1-3、 Homer1、CaMK2α、NRXN1、NLGN2、Drebrin1、ARHGAP32 和 Dock9 在内的 PSD 相关蛋白下调（经 FDR 调整的 P < 0.05）。相比之下，ASD 成年个体的 PSD 相关改变则不那么严重或不变。网络分析显示谷氨酸受体异常。总体而言，蛋白质组学数据支持特发性自闭症是一种涉及 PSD 相关 ASD 风险基因的突触病的概念。前额叶皮层 PSD 复合物进化保守的缓慢成熟过程中断，可能导致易感个体发生 ASD。
